Women Researchers in NF – Conxi Lazaro

Three Decades in the NF Community: A Journey of Discovery, Collaboration, and Advances

Conxi Lazaro, PhD, Head, Molecular Diagnostic Service, Hereditary Cancer Program, Catalan Institute of Oncology – IDIBELL

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1. Hereditary Cancer Program, Catalan Institute of Oncology, Institut d’Investigació Biomèdica de Bellvitge – IDIBELL-ONCOBELL, 08908, L’Hospitalet de Llobregat, Spain
2. Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain

Acknowledgements:

Many thanks to all current and past members of my team for their work and time dedicated to improving knowledge in the NF1 field. Thanks to all the collaborators of the Barcelona Neurofibromatosis clinical and research group (CSUR Phacomatoses and Genturis).  I also thank all the patients who generously donated a tumor sample to generate the mouse models developed in our platform. I want to thank all Spanish NF patients and NF associations for their continuing support and effort, in particular the Spanish Asociación de Afectados de Neurofibromatosis (AANF) and the Associació Catalana de les Neurofibromatosis (ACNefi).

Funding:

I would particularly like to acknowledge the financial support of the Fundación PROYECTO NEUROFIBROMATOSIS (FPNF), Children Tumor Foundation (CTF), Gilbert Family Foundation, NTAP, and NF Research Initiative.  In addition, I would like to also acknowledge the support provided by the Fondo de Investigación Sanitaria Española – Instituto de Salud Carlos III (RTICC, CIBERONC) and the Catalan Health Institute – Government of Catalonia. Contract grant numbers: RD06/0020/1051, RD06/0020/1050, RD12/0036/0008, RD12/0036/0031, PI10/01422, PI10/0222, PI11/01609, PI12/01528, PI13/00285, PIE13/00022, PI13-01339, PI23/00017, PI19/00553 and SAF2010-21165, SAF2013-45836-R, 2009SGR283, SGR290, SGR1465, and 2023SGR01112. I thank the CERCA Programme / Generalitat de Catalunya for institutional support.

A few months ago, when I received an invitation to write an essay reflecting on my experience in the NF community, I felt an inner tingle and was transported to when I was twenty-two years old, in the penultimate year of my bachelor’s degree in biology. I always say that I studied biology because, in the 80s in Spain, that was the degree that offered the most subjects related to genetics. In high school, I discovered genetics from Gregor Mendel’s experiments with his peas and his results based on the tables of possible interbreeding and the laws of heredity fascinated me. In the fourth year of my degree, a brilliant young researcher gave us a master class in positional cloning, giving as an example the search for the gene responsible for cystic fibrosis, a project he was working on at the time. That researcher was Dr. Xavier Estivill, the energy and enthusiasm he transmitted in presenting his work made me decide to work with him and learn from his group. That’s how I started as a summer student in his group in 1989. The following year, having just graduated, I started my thesis by helping a dermatologist (Anna Ravella) to study families with Neurofibromatosis type 1 (NF1). Needless to say, I had never heard of this disease. My mentor told me that it was a common disease, although rare, that the gene had not yet been identified, and that there was a lot of work to do in this field. The proposal was to carry out two doctoral theses, one from a clinical point of view (Anna) and the other from a laboratory perspective (mine). In July 1990, Drs. Collins and White & O’Connell’s groups simultaneously published the identification of the gene responsible for NF1 [1, 2]. A new stage had begun in the genetic study of this disease and we were first-line witnesses. The beginnings were not easy, the description of the gene was incomplete, there was only information for nine coding exons, the study techniques were expensive and time-consuming, and the search for genetic markers was needed for genetic linkage studies. It was a time of great learning, of positive results but also setbacks and difficulties. Thus, in the first years of my thesis, I dedicated myself to looking for intragenic markers of the microsatellite type to facilitate genetic linkage in familiar cases, as well as implementing a technology, at that time novel, named SSCP (single-strand conformation polymorphism), for the study of the first nine exons described for this gene [3].  During my thesis, I had the honor of being able to attend my first congresses, both national and international. My first NF congress was in Oxford in 1992, and my first trip to the USA was to attend the American NF Congress in Ann Arbor, Michigan in 1993, hosted by Dr. Francis Collins. These congresses allowed me to meet great researchers in the field of neurofibromatosis as well as young and emerging researchers with whom I shared projects and collaborations as well as dinners and moments of fun. The result of these years was the presentation of Dr. Ravella’s thesis in 1992 and mine in 1995. I would like to thank Anna Ravella, Antonia Gaona, Helena Kruyer, Carolina Gómez, Teresa Casals, and Víctor Volpini for their work and support, and especially my thesis supervisor, Xavier Estivill. My thesis compiled my five-year research on improving the genetic diagnosis of NF1 in our population, the identification of various point mutations, the characterization of several microsatellite markers, together with our experience in prenatal diagnosis and the identification and molecular confirmation of a case of paternal genetic mosaicism [4-13].

Dr. Lazaro’s First Aspen Meeting

As fate would have it, I was given a small project for the genetic study of neurofibromas just as I finished my doctoral thesis, the project only had enough funding to hire one doctoral student and that was Eduard Serra. In addition, together with my thesis supervisor, Xavier Estivill, I co-directed Elisabet Ars’ thesis at the same time. These post-thesis years had a great impact on our consolidation as an NF group in our country, which allowed us to make important contributions to the field of improving genetic diagnosis (Dr. Ars’s thesis), as well as to the genetic bases of benign dermal neurofibromas (Dr. Serra’s thesis). Elisabet developed the study of the complete NF1 gene from RNA, dramatically changing the diagnostic yield for NF1 in our center and contributing significantly to deepening our knowledge of the genotype-phenotype relationships in this disease [14-18]. Eduard presented a great thesis studying the genetic, molecular, and cellular bases of cutaneous neurofibromas, making paramount discoveries and publications in the field [19-22]. Those years were of great intellectual stimulation and huge challenges and discoveries, we will never forget the wonderful congresses in Aspen, the charm of the Jerome Hotel, and how we were part of the great international NF community. During all this time I obtained national funding to continue with my working group in NF1, a field to which I have dedicated myself with greater or lesser intensity over the last three decades. After my two first theses as a supervisor, new additions to the group allowed us to continue with the study of the mutational spectrum of the NF1 gene as well as to explore the use of antisense oligonucleotides as a therapeutic strategy for this disease, work carried out by Eva Pros, Eva Toledano, and Juana Fernandez [23-26]. Our work has always been focused on improving genetic testing and treatment for NF1 patients. On a clinical level, the incorporation of Ignacio Blanco and Héctor Salvador into the group was a fundamental milestone towards achieving national and European clinical recognition and thus becoming a Spanish reference center (CSUR in phacomatosis) as well as belonging to the European Genturis network. With time, the molecular diagnosis of neurofibromatosis in our group was moved to another campus and was co-led by Dr. Serra and myself thanks to the incorporation of Drs. Elisabet Castellanos and Bernat Gel. With them, we were able to move on to next-generation sequencing by designing an ad-hoc panel covering all hereditary cancer syndromes [27], including genes for all neurofibromatosis-related syndromes.

In the last fifteen years, I have focused on the genetic diagnosis of hereditary cancer and the molecular diagnosis of cancer in general, so my dedication to research has been reduced. However, the opportunity to have Dr. Serra as a senior postdoc in my group gave rise to the possibility of opening new lines of research, which also led Eduard to form his own group and continue our collaboration as an independent principal investigator. The incorporation of Dr. Juana Fernández and a graduate student, Joan Castellasagé, into my group, together with Dr. Alberto Villanueva’s knowledge of the development of PDOX animal models, has led to a new research line for my team, focused on the development of a preclinical platform of PDOX cell lines and murine models from primary MPNSTs tumors of patients in our environment [28]. In recent years, we have strengthened our platform and have carried out multiple scientific collaborations both in the academic field and with private companies or spin-offs. Our current fellows, Edgar Creus and Sara Ortega, are doing an excellent job in improving the characterization of the platform [29, 30], and our ongoing collaboration with Dr. Eduard Serra’s group allows us to participate in several projects on molecular MPNST characterization. As I write this short review, it fills me with pride to see how great researchers, who began their journey with us, have grown. I want to thank Dr. Serra’s current group, with whom we have a close collaboration that has yielded very interesting scientific results thanks to the work of Meritxell Carrió, Helena Mazuelas, Miriam Magallón, Itziar Uriarte, Carles García-Linares, Josep Biayna, and Ernest Terribas [31-37].

For me, these more than 30 years in the NF community have allowed me to witness first-hand the evolution and advances in this group of rare diseases in multiple aspects of both basic and clinical research, as well as changes in the clinical management of patients. I have been able to participate in different consensus guidelines and collaborative efforts that have improved the clinical management of our patients [38-47]. The active collaboration of patient associations has always been a driving force that has guided our professional objectives and research projects, listening to their concerns and needs [48, 49]. Here, I want to thank all the national and international associations in this field for their great involvement and dedication. I also want to thank the patient foundations that have given us financial support to carry out our projects (Spanish Neurofibromatosis Project Foundation, CTF, NTAP, Gilbert Foundation, ACNefi), as well as the various national organizations that have funded our research (Spanish Ministry of Health and Science, Fundació Marató de TV3). In recent years, the scientific community has grown and there have been important advancements in knowledge; this has allowed us to have better diagnostic tools, develop new therapeutic strategies, and generate resources and knowledge that can be used transversally, not just by our community but by the entire scientific community in general.

I want to end by thanking the entire international NF family but especially the researchers who helped me in the early days and with whom I have collaborated on different projects and initiatives such as Eric Legius, Meena Upadhyaya, Ludwine Messiaen, Kati Wimmer, Peggy Wallace, Thomas de Raedt, Gareth Evans, Hildegard Kehrer-Sawatzki, Pierre Wolkenstein, Juha Peltonen, Thorsten Rosenbaum,  Nancy Ratner, Andre Bernards, Jim Gusela, Jim Walker, Hilde Brems, Catalina López-Correa, Peter Bellerman, Bruce Korf, Annette Bakker, Patrice Pancza, and in general to the entire NF community; I am sorry if I have left anyone off the list. I also want to thank all the members of my present and past team, as well as Dr. Serra’s team, the Spanish NF1 patients and their clinicians, their families, and the associations and foundations that have helped us to do our bit in this stimulating field of knowledge, where much progress has been made but with a future full of obstacles and challenges.

I would like to express my gratitude for the opportunity to participate in European and CTF meetings, as well as for the privilege of co-chairing the EU Neurofibromatosis meeting in 2014 and the CTF Conference in 2020.  I am also deeply honored to have received the Theodor Schwann Award in 2016.

I want my last words to be of remembrance, thanks, and recognition to a great researcher and also a great person in the field of NF, who unfortunately left us recently, Dr. Ludwine Messiaen. Ludwine was a pioneer in the field of the genetic diagnosis of NF1 and other related diseases. She participated in numerous international publications of great relevance to our field of study [50-53]. Ludwine was a great professional, demanding, and meticulous in her work, but she also had great personal and humanistic values, an artist’s soul, and an unquestionable elegance. I want to end with a few lines from a Catalan poet, Enric Casasses, in her memory:

“Not having met you
It would be terrible
but terrible, terrible
And I wouldn’t know it
On top of that, I wouldn’t know it”

About Conxi Lazaro, PhD

Dr. Conxi Lazaro is a molecular geneticist with more than 25 years of experience in the field of human genetics. She did her PhD in Human Genetics at University of Barcelona. She has worked in several clinical hospitals in Barcelona. She was an invited professor at Massachusetts General Hospital Cancer Center at Boston in 2003/04 and did a sabbatical stay at Mount Sinai Hospital and at Women’s College Hospital in Toronto in 2018/19. In the last ten years she has been involved in several projects aimed at using Next Generation Sequencing (NGS) for genetic testing purposes. Her field of expertise is Hereditary Cancer. Of relevance was her pivotal research in the genetic basis of Neurofibromatosis type 1 (NF1) and related tumors. She is member of several reputable international consortia and associations such as CIMBA, ENIGMA, CTF, GENTURIS.

She received the Theodor Schwann Award in 2016.

Dr. Lazaro was co-chair of the 16th European Neurofibromatosis meeting in 2014 and co-chair of 2020 CTF Conference.

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